Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet.

Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor (RXR) gamma isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXRgamma-deficient (-/-) mice had lower fasting plasma TG levels compared with wild-type littermates (33.1 +/- 2.0 vs. 51.7 +/- 6.3 mg/dl, respectively; P < 0.05). Skeletal muscle LPL activity was higher in RXRgamma mice (18.7 +/- 2.2 vs. 13.3 +/- 1.3 nmol free fatty acids/min.g; P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXRgamma in skeletal muscle. In addition, when exposed to a 14-wk high-fat diet, RXRgamma -/- mice had less weight gain, which was entirely due to lower fat mass (11.9 +/- 1.8 vs. 14.4 +/- 1.1 g; P = 0.01), and leptin levels were also lower in the RXRgamma -/- mice (17.6 +/- 5.0 vs. 30.9 +/- 6.4 ng/ml; P = 0.03). These data suggest that RXRgamma -/- mice are resistant to gain in fat mass in response to high-fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.